Catalytic Synthesis of Heterocycles via the Cleavage of Carbon ─ Heteroatom Bonds Takuya Kodama, Naoto Chatani, and Mamoru Tobisu ＊

＊ Department of Applied Chemistry, Graduate School of Engineering, Osaka University 2 ─ 1 Yamkada ─ oka, Suita 7565 ─ 0871, Japan

(Received July 23, 2018; E ─ mail: [email protected])

Abstract: Catalytic synthesis of heteroles via the cleavage of carbon ─ heteroatom bonds is described. The rho- dium ─ catalyzed reaction of 2 ─ silylphenylboronic acids with internal alkynes gives 2,3 ─ disubstituted benzosi- lole derivatives with loss of a substituent in the triorganosilyl group of the staring material. π ─ Extended phos- pholes and thiophenes were found to be synthesized by the palladium ─ catalyzed reactions of normally unreactive tertiary phosphines and sul des through the cleavage of carbon ─ phosphorus and carbon ─ sulfur bonds, respectively. In addition, double cleavage of carbon ─ phosphorus bonds of bisphosphines is found to occur with the generation of phospholes.

1． Introduction Scheme 1. Reported and unreported methods for carbon ─ heteroatom bond formation. Although the majority of organic molecules are comprised of the rst row elements, including carbon, hydrogen, oxygen and nitrogen, current chemists are now able to study an even more diverse range of molecules by introducing heavier ele- ments, such as silicon, phosphorus and sulfur. Each of these elements has speci c characteristics that are completely differ- ent from the rst row elements, thereby frequently leading to the discovery of molecules with unique biological and opto- electronic properties. For example, thiophenes, 1 siloles, 2 and phospholes, 3 often referred to as heteroles 4 in a broader sense, have emerged as scaffolds of great interest for their ability to tune the properties of π ─ systems by characteristic interactions with embedded heteroatoms. Despite the increasing demand of these types of heterole derivatives, their synthesis still heav- ily depends on classical substitution reactions between carban- ions and heteroatom ─ based electrophiles, which limits the scope of heterocycles that can be produced. When developing heterole synthesis via carbon ─ heteroatom bond cleavage. new methods for producing such heteroles, the key issue is how 2． Cleavage of Carbon Silicon Bonds to forge carbon ─ heteroatom bonds. In addition to classical ─ organometallic substitution using electrophilic reagents con- Organosilicon compounds have played pivotal roles in taining an E ─ X bond (E=Si, P and S) (Scheme 1a), catalytic organic synthesis as synthetic reagents as well as in optoelec- 5 carbon ─ heteroatom bond forming reactions have now become tronic materials. The development of a new synthetic strategy powerful methods for constructing heterole skeletons. In these for the transformation of carbon ─ silicon (C ─ Si) bonds would, reactions, heteroatom ─ hydrides (E ─ H), such as hydrosilanes, therefore, be highly desirable. However, C ─ Si bonds are gener- hydrophosphines and thiols, can serve as sources of a hetero- ally thought to be unreactive and extremely harsh conditions 6 atom that is coupled with aryl halides or arenes (Scheme 1b). are normally needed to activate them. The reactivity of C ─ Si We envisioned that, if were possible to use fully carbon ─ substi- bonds depends on the hybridization mode of the carbon atoms 2 tuted organosilicon, phosphorus and sulfur compounds in that are attached to silicon. C(sp ) ─ Si, C(sp) ─ Si and C(allyl) ─ 3 catalytic carbon ─ heteroatom bond formation reactions, this Si bonds are relatively easy to cleave compared with a C(sp ) ─ would represent a new alternative to the classical methods that Si bond because of the hyperconjugation effect with neighbor- 7 3 are currently in use (Scheme 1c). For this to be realized, an ing π ─ bonds. C(sp ) ─ Si bonds that are incorporated in a obvious issue that needs to be addressed is a method for the strained ring, such as silacyclopropanes 8 and silacyclobutanes, 9 cleavage of carbon ─ heteroatom bonds, which is an uncommon are exceptionally reactive, affording ring ─ opened products process. Although our motivation to develop these types of under mild conditions. A common strategy for activating 3 reactions centered on our fundamental interest in the catalytic unstrained C(sp ) ─ Si bonds involves the conversion of tetraor- activation of carbon ─ heteroatom bonds, we also expected that ganosilicon compounds to penta ─ or hexacoordinated silicon these reactions would provide a nontrivial synthetic advantage, species by adding an external or internal nucleophile. 10 For such as late ─ stage functionalization and avoiding the use of example, the addition of a uoride anion to a tetraorganosili- undesirable and unpleasant reagents (corrosive, pyrolytic, con compound results in the formation of a pentacoordinated - odor). We report in this account on our progress in catalytic Me 3SiF 2 species, an Me ─ Si bond of which can be activated by

Vol.76 No.11 2018 （ 49 ） 1185 a palladium catalyst. This process is used as a methylation benzosilole derivatives with functional groups to be con- 11 method in cross ─ coupling reactions. Other nucleophiles, such structed by simply changing the structure of the alkyne cou- as alkoxides 12 and carbonyl groups 13 can also be used to acti- pling partners. 3 vate C(sp ) ─ Si bonds, when they are tethered to the organosili- 14 con substrates. Strong carbon nucleophiles, such as organo- Scheme 3. The rhodium ─ catalyzed synthesis of benzosiloles via the lithium and organomagnesium reagents, can also promote reaction of 2 ─ (trimethylsilyl)phenyl boronic acid with 3 various alkynes. substitution at the silicon center with the cleavage of C(sp ) ─ Si bonds, when the process is an intramolecular reaction. 15 As 3 described thus far, the activation of unstrained C(sp ) ─ Si bonds requires the use of strong nucleophiles to form reactive penta ─ or hexacoordinated silicon species. A notable exception to this is a report by Ojima in 1992 on the rhodium ─ catalyzed t reaction of the diyne1 with HSi BuMe 2, leading to the forma- tion of the silole derivative 2, in which a Me ─ Si bond under- goes cleavage in the absence of strong nucleophiles (Scheme 2). 16 Despite its mechanistic implications and poten- tial utility for the catalytic synthesis of silole derivatives, this report includes only one isolated example, and additional investigations related to this reaction have not been reported.

Scheme 2. An early example of the catalytic activation of 3 unactivated C(sp ) ─ Si bonds.

In 2009, our group reported on the rhodium ─ catalyzed activation of a carbon ─ silicon (C ─ Si) bond in the synthesis of 17 benzosilole derivatives (Scheme 3). The reaction of 2 ─ tri- methylsilylphenylboronic acid 3 with an internal alkyne in the presence of a [RhCl(cod)] 2 catalyst and DABCO as a base gave a 2,3 ─ disubstituted benzosilole. In this reaction, the product is formed with a loss of a methyl group of a trimethysilyl group. This reaction is initiated by the transmetallation of the starting boronic acid 3 to rhodium(I) hydroxide, which is generated in situ, to form an arylrhodium(I) species 5. The subsequent insertion of an alkyne into the carbon ─ rhodium bond in 5 leads to the formation of the alkenylrhodium 6. Cyclization would then occur with the cleavage of a C ─ Si bond in a trimethylsilyl group to furnish the desired benzosilole 7 along with a methylrhodium species, which, on protonation, regene- rates rhodium(I) hydroxide. The scope of alkynes used for this catalytic benzosilole synthesis is shown in Scheme 3, where internal alkynes bearing aliphatic and aromatic substituents both participate in the reaction successfully. Functional groups, including ketones, esters and even bromides are com- patible with this protocol, allowing for the further elaboration of the products. Regarding the regioselectivity of the reaction with asymmetrical alkynes, more sterically hindered groups The effect of SiR 3 groups of the boronic esters was further tend to be preferentially introduced at the α ─ position of the investigated to elucidate the mechanism responsible for C ─ Si silicon, as exempli ed in the formation of alkyl phenyl acety- bond activation (Scheme 4). The ndings revealed that a trieth- lenes and alkyl trimethylsilyl acetylenes. In the case of alkynes ylsilyl group also participated in the reaction with the elimina- bearing an ester group, the ester group is incorporated at the tion of an ethyl group, although the yield was slightly lower α ─ position of the silicon atom regardless of the steric bulki- than that when a methyl group is cleaved (entry 1). A substrate ness of the substituent at the other side. In the eld of organic bearing both a methyl and an n ─ butyl group on the silicon materials development, synthetic methods that allow access to atom provided two benzosilole derivatives, in which the cleav- n a library of benzosiloles bearing various functional groups are age of a Si ─ Me bond was favored over a Si ─ Bu bond (93/7) desired. In this context, this reaction, in fact, permits various (entry 2). A Si ─ Me bond was cleaved exclusively when a sub-

1186 （ 50 ） J. Synth. Org. Chem., Jpn. strate bearing both methyl and isopropyl groups on the silicon Scheme 5. Proposed mechanisms for rhodium ─ catalyzed C ─ Si bond activation. atom was used (entry 3). A substrate bearing a SiMe 2Ph group provided two isomeric benzosilole derivatives, in which either the Si ─ Me or the Si ─ Ph bonds were cleaved in a ratio of 59/41 (entry 4). This result is in sharp contrast to the results for C ─ Si bond cleavage reactions that proceed via penta ─ or hexacoor- dinated silicate species, in which the cleavage of a Si ─ Ph bond is favored over a Si ─ Me bond. A SiMePh 2─ substituted sub- strate also participated in this annulation reaction through the exclusive cleavage of a Si ─ Ph bond (entry 5). Based on the order of reactivity of a series of C ─ Si bonds, two mechanisms that do not involve silicate ─ type intermediates are proposed (Scheme 5). In the case of substrates bearing trialkylsilyl groups, an alkenylrhodium species 11 undergoes C(alkyl) ─ Si bond cleavage via σ ─ bond metathesis through a four ─ mem- bered cyclic transition state, in which a less hindered group would be expected to be more easily cleaved (pathway a). The oxidative addition of a C(alkyl) ─ Si bond involving a 18 rhodium(III) intermediate, however, also cannot be excluded. The synthesis of a 1,5 ─ dihydro ─ 1,5 ─ disila ─ s ─ indacene Concerning the cleavage of a C(aryl) ─ Si bond, it was revealed derivative is shown in Scheme 6. 1,4 ─ Dibromobenzene (16) is that electron ─ rich aryl groups are more susceptible to cleavage rst converted to a disilyl ─ substituted phenylboronate ester 17 than electron ─ poor aryl groups, suggesting that the reaction via an ortho lithiation protocol. The sequential formation of proceeds through an asynchronous electrophilic aromatic sub- silole rings by annulation with two different alkynes led to the stitution mechanism involving an arenium ion ─ like intermedi- formation of the asymmetrically ─ substituted π ─ system 21. ate 14. The key to the success of this synthesis is the tolerance of a bromo moiety in our rhodium ─ catalyzed formation of a silole Scheme 4. Scope of silicon substituents. derivative, which allows the bromide to serve as a handle for the second rhodium ─ catalyzed annulation.

Scheme 6. Synthesis of an asymmetrically substituted 1,5 ─ dihydro ─ 1,5 ─ disila ─ s ─ indacene derivative by the sequential introduction of two different alkynes.

The selective cleavage of asymmetrically substituted silyl groups provided us with an opportunity to examine the cata- lytic enantioselective construction of a silicon stereogenic cen- ter using this method. In fact, the use of a chiral ligand (S,S) ─ QuinoxP ＊ 24 in the rhodium ─ catalyzed annulation of a sub- i strate bearing a SiMe 2 Pr group leads to the chemo ─ and enantioselective cleavage of a Me ─ Si bond to give a benzosilole 17b product with a Si ─ centered chirality (Scheme 7a). Germoles, a heavier congener of siloles, have also emerged as a potential scaffold for use in preparing molecular ─ based 19 materials including aggregation ─ induced emission materials 20 and components of p ─ type semiconductors. Our group

Vol.76 No.11 2018 （ 51 ） 1187 Scheme 7. (a) Rhodium ─ catalyzed enantioselective C ─ Si activation esters with alkynes in the presence of a rhodium(I) catalyst and (b) C ─ Ge activation. similarly proceeded to give benzogermole derivatives (Scheme 7b). Additional reactions involving catalytic C ─ Si bond cleav- age have been reported by several other groups (Scheme 8). Matsuda reported on the rhodium ─ catalyzed silylative annula- tion of alkynes with hexamethyldisilane, which afforded fully ─ substituted silole derivatives (Scheme 8a). 23 In this reaction, the use of a rhodium complex ligated by a norborna ─ 2,5 ─ diene improved the yield of the cyclization product. Xi reported on a palladium ─ catalyzed variant of our benzosilole synthesis, in which aryl halide ─ based substrates were used instead of aryl- 24 boron compounds in an intra ─ (Scheme 8b) and intermolecu- lar (Scheme 8c) 25 annulation with internal alkynes. Shirakawa Scheme 8. Other catalytic syntheses of silole derivatives via C ─ Si and Hayashi reported on the iron ─ catalyzed synthesis of ben- 26 bond cleavage. zosilole derivatives via C ─ Si bond cleavage (Scheme 8d). In this reaction, ortho ─ trimethylsilylaryllithium adds across an

alkyne in the presence of Fe(acac) 3 to form an alkenyllithium intermediate, which subsequently attacks the silicon center in an intramolecular manner, resulting in C ─ Si bond cleavage via a silicate intermediate. He’s group reported rhodium ─ catalyzed synthesis of heteroarene ─ fused silole derivatives by tandem cyclization of ortho ─ alkynylphenols and ─ anilines, followed by 27 cyclization via C ─ Si bond cleavage (Scheme 8e). 3． Cleavage of Carbon ─ Phosphorus Bonds Phospholes and their benzo ─ fused derivatives have recently received signi cant attention because of their unique optoelec- tronic properties. 28 The most common approach for the syn- thesis of phospholes is the substitution of a phosphorus ─ halo- gen (P ─ X) bond with a stoichiometric amount of an organometallic species such as an organolithium or an organo- magnesium reagent. However, the strong nucleophilicity of these reagents signi cantly limits the scope of the phospholes that can be accessed by this method. Therefore, the deve- lopment of functional group tolerant, catalytic methods for the construction of phospholes will be needed. The catalytic formation of phosphople derivatives was rst reported in the synthesis of helicene analogs of phospholes by the rhodium ─ catalyzed [2+2+2] cycloaddition of dialkynylphosphines to polyynes. 29 A more general approach to the catalytic synthesis of phospholes involves catalytic C ─ P bond formation reac- tions. The intramolecular cross ─ coupling of hydrophosphines with aryl halides or their synthetic equivalent have been used for the synthesis of phosphole derivatives (P ─ H/C ─ X coupling) 28h (Scheme 9a). The palladium ─ catalyzed intramolecular dehy- drogenative phosphination of C ─ H bonds using hydrophos- phine oxide was also developed (P ─ H/C ─ H coupling) 30 (Scheme 9b). This method has some advantages over the P ─ H/C ─ X coupling method since the starting materials are more readily available. applied the rhodium ─ catalyzed annulation strategy of organo- The widespread availability, stability and ease of handling silicon compounds to preparing the corresponding organoger- of tertiary phosphines prompted us to develop catalytic meth- manium compounds, which allowed the successful synthesis of ods for their conversion them to phosphole derivatives via C ─ P germoles via the activation of a carbon ─ germanium (C ─ Ge) bond cleavage. Organolithium reagents were reported to pro- 21 2 bond. Although the activation of C(sp ) ─ Ge bonds is known, mote the cleavage of a C ─ P bond of a tertiary phosphine moi- as represented by palladium ─ catalyzed cross ─ coupling using ety in an intramolecular manner to form phospholes - 22 31 an in situ generated pentavalent germanate (ArGeMe 2F 2 ), (Scheme 10a). Although these methods are known, the cata- 3 the corresponding activation of unactivated C(sp ) ─ Ge bonds lytic synthesis of phospholes via C ─ P bond cleavage had not 32 34 has never been reported. Analogous to the rhodium ─ catalyzed been reported when we initiated our study in 2012. ─ It was the silole synthesis, the reaction of 2 ─ germlyphenylboronic also reported in 2015 that the reductive cleavage of a C ─ P

1188 （ 52 ） J. Synth. Org. Chem., Jpn. Scheme 9. Catalytic C ─ P bond formation in the synthesis of phosphole by treatment with a Pd(0) complex. It is important phospholes. to note that phosphonium salt 51 serves as an internal oxidant for regenerating the Pd(II) species from Pd(0). Since dibenzo- phosphole 52 is susceptible to oxidation during its isolation, the products were isolated as the corresponding oxides by

treatment with H 2O 2 or air. This strategy could be applicable to a wide variety of biphenylphosphine derivatives that possess electronically different functional groups, including ethers, amines, ketones, esters, nitriles, and uorides. It should also be noted that biphenylphosphines bearing chloro and bromo groups could also be converted to the corresponding phospho- les with the halogen groups remaining intact, which permits further synthetic elaboration of the phosphole skeleton based on C ─ X bond functionalization. This cyclization also proceeds when substrates bearing an ortho ─ substituent are used (i.e., 53j and 53k), whereas substrates with meta ─ substituents under- went regioselective cyclization at the less hindered site (i.e., bond of a triarylphosphine derivative by metallic lithium can generate a phosphorus ─ centered anion, which can then be 35 Scheme 11. Palladium ─ catalyzed synthesis of dibenzophosphole used for the synthesis of phospholes (Scheme 10b). derivatives.

Scheme 10. Anionic C ─ P bond cleavage in the synthesis of phospholes.

Our success in the catalytic synthesis of siloles via C ─ Si bond cleavage, as described in section 2, naturally led us to investigate the possibility of expanding the reaction to corre- sponding phosphorus variants. However, a simple extension of the rhodium ─ catalyzed silole synthesis (Scheme 3) to the syn- thesis of phospholes using triphenylphosphines bearing an ortho boryl group was not successful. After numerous experi- ments, it was found that dibenzophospholes can be synthesized by simply heating the biarylphosphine 49 in the presence of a 36 Pd(OAc) 2 catalyst (Scheme 11). In this reaction, both C ─ P and C ─ H bonds in 49 are cleaved, thereby allowing simple ter- tiary phosphines bearing no reactive functional groups to serve as starting materials for the synthesis of phospholes. The reac- tion appears to proceed through 1) the cyclopalladation of 49 to form palladacyle 50, 2) the C ─ P bond ─ forming reductive elimination of 50 to generate the phosphonium salt 51, and 3) the oxidative addition of a C ─ P bond in 51 to give the phos- phole 52. The eliminated PhPd(OAc) species can be protonated by HOAc to regenerate Pd(OAc) 2. The intermediacy of a phosphonium 51 species is supported by the fact that an inde- pendently synthesized phosphonium gave the corresponding

Vol.76 No.11 2018 （ 53 ） 1189 53l). This method allows various π ─ systems, including naph- Scheme 13. Palladium ─ catalyzed synthesis of six ─ membered thalene, phenanthrene, furan, pyrrole and pyridine, to be phosphacycles. incorporated to a phosphole motif, thus making a series of elaborate ring systems readily accessible. The functionalized phospholes described here can be sub- jected to further elaboration. For example, the Suzuki ─ Miyaura reaction of the bromophosphole 53i followed by 37 catalytic C ─ H amination leads to a molecule with extended π ─ conjugation, as in 55 (Scheme 12).

Scheme 12. Synthetic elaboration of 53i.

Despite the signi cant interest in the phosphole derivatives described above, the chemistry of the corresponding six ─ mem- bered phosphacycles has remained underdeveloped, partly due to the fact that only limited methods for their preparation are available. Our group then applied the C ─ P bond cleavage strategy to the construction of six ─ membered phosphacycles. We initially examined the palladium ─ catalyzed reaction of phosphine 56’ under the conditions developed for the synthesis of phosphole derivatives, but the desired cyclized product was not produced and the starting material was recovered quantita- tively (Scheme 13). We surmised that the failure could be attributed to the dif culty in forming a seven ─ membered metallacyclic intermediate compared with the six ─ membered Further studies in our group led us to develop a new intra- intermediate that is involved in the synthesis of phosphole molecular C ─ P/C ─ P cross ─ coupling method for the synthesis derivatives. of phosphacycles, which allows commercially available bispho- To address this issue, we used the halide 56 as a substrate, sphines to be cyclized via the cleavage of two C ─ P bonds 39 which would form the required seven ─ membered palladacycle (Scheme 14). For example, the reaction of BINAP in the 57 via oxidative addition to Pd(0). By optimizing the reaction presence of an [(allyl)PdCl] 2 catalyst gives π ─ extended phos- conditions, we found that the desired six ─ membered phospha- pholes with the loss of PPh 3. It is important to note that this cycle products can, in fact, be generated from the halide 56 in BINAP ─ derived phosphole cannot be synthesized either by the the presence of a catalytic amount of Pd(OAc) 2 in DMF at C ─ H/C ─ P or C ─ X/C ─ P coupling methods shown in Schemes 130 ℃ in the presence of an appropriate reductant 11 and 13. Although a detailed mechanism for this reaction (Scheme 13). 37 Among the reductants examined, the bulky remains elusive, the reaction is likely to be initiated by the oxi-

(Me 3Si) 3SiH was found to be most effective. In this reaction, dative addition of an Ar ─ PPh 2 bond in 61 to Pd(0) to form the the cyclization proceeds in a similar manner to that depicted in seven ─ membered palladacycle 62. A subsequent C ─ P bond Scheme 11. The reductive elimination of the palladacycle 57 to forming reductive elimination gives the phosphonium salt 63 form the phosphonium derivative 58, followed by oxidative along with Pd(0). The C ─ Ph bond of 63 is cleaved via oxidative addition of 58 to Pd(0) leads to the formation of the phospha- addition to Pd(0), releasing the phosphacycle 64, along with cycle 59, along with PhPdX. To complete the catalytic cycle, PhPdPPh 2, which ends up with the formation of PPh 3 and the PhPdX needs to be reduced to Pd(0), which calls for the Pd(0). It should be noted that Morandi’s group independently addition of a suitable reducing agent. The steric bulk of reported on a similar reaction using a Pd 2(dba) 3/PhI catalyst 40 (Me 3Si) 3SiH serves to reduce the PhPdX species in preference system. Various bisphosphines having a biaryl skeleton can to 56. As shown in Scheme 13, a wide range of six ─ membered be converted to the corresponding phospholes in one step by phosphacycles, particularly, those bearing functional groups simply treating with a palladium catalyst. In addition, six ─ that are incompatible to the classical method using carbanion membered phosphacycles can also be prepared from the corre- species, can be synthesized successfully using this method. sponding bisphosphines.

1190 （ 54 ） J. Synth. Org. Chem., Jpn. Scheme 14. Palladium ─ catalyzed cyclization of bisphosphines to calixarenes bearing a phosphole scaffold was accomplished phosphacycles via the cleavage of two C ─ P bonds. using these methods (Scheme 16). 43 These molecules have the potential for serving as advanced ligands and uorescent mate- rials with the ability to interact with a range of guest molecules.

Scheme 16. Synthesis of calixarenes bearing a phosphole scaffold.

4． Cleavage of Carbon ─ Sulfur Bonds Thiophenes and their π ─ extended derivatives represent scaffolds of great importance, especially in the eld of materi- als chemistry, and therefore the method development for pre- paring these compounds continues to be vibrant. 44 When assembling a thiophene ring, odorous sulfur reagents, such as thiols and sulfur itself, are frequently used. We envisioned that Since the publication of our ndings, a related catalytic sul des could serve as a more benign source of sulfur for the reaction that permits the synthesis of phosphole derivatives synthesis of thiophene derivatives, provided that a suitable C ─ appeared. Wang reported on the Pd(II) ─ catalyzed oxidative S bond cleavage reaction could be developed. Based on our annulation of tertiary phosphines with internal alkynes to success in the palladium ─ catalyzed synthesis of phospholes form phosphonium salts, which further supports the interme- derivatives via intramolecular C ─ P/C ─ H coupling (Scheme 17), diacy of a phosphonium salt in our catalytic reactions we initially investigated the possibility of developing such a 41 (Scheme 15a). Mathey reported on the Pd/Cu ─ catalyzed sulfur variant. Although a C ─ H activation strategy has been cyclization of triarylphosphines bearing an ortho ─ alkynyl used for the construction of a thiophene scaffold (Scheme 17a ─ 45 48 group, in which one of the aryl groups at the phosphorus cen- c), ─ C ─ S/C ─ H cross ─ coupling (Scheme 17d), which we were ter is transferred to the 3 ─ position of the phosphole ring interested in achieving, has not been reported. Unlike the other 42 (Scheme 15b). The methods developed by our group and by strategies, C ─ S/C ─ H coupling would not require, in principle, Mathey can be used for introducing a fused phosphole into the use of stoichiometric amounts of oxidants and organic complex functional molecules. For example, the synthesis of halides. The desired reaction, in fact, proceeded under Scheme 15. Recent reports on the catalytic synthesis of palladium(II) ─ catalyzed conditions when a biaryl sul de 75 49 phosphacycles by other groups. was used. The addition of bulky benzoic acid derivative (2,6 ─

Me 2C 6H 3CO 2H) was found to improve the yield signi cantly. Regarding the leaving group on the sulfur atom, the use of a phenyl group is essential for an ef cient reaction, with only 7% of the product being formed when a substrate bearing a

methylthio group was used. In this reaction, Pd(OCOAr) 2

(Ar=2,6 ─ Me 2C 6H 3), generated by the ligand exchange of

Pd(OAc) 2 with ArCO 2H, reacts with 75 to form the palladacy- cle 76 via sulfur ─ directed cyclometallation. The C ─ S bond cleavage process is likely to occur through a sulfonium inter- mediate, similar to the phosphonium salts involved in the cata- lytic synthesis of phosphole derivatives (Schemes 11 and 13). Thus, the C ─ S bond forming reductive elimination from 76

Vol.76 No.11 2018 （ 55 ） 1191 Scheme 17. Catalytic approaches to benzo ─ fused thiophenes via Scheme 18. Palladium ─ catalyzed synthesis of dibenzothiophene C ─ H activation. derivatives via the cleavage of C ─ S and C ─ H bonds.

provides a dibenzosulfonium cation 77 and a Pd(0) fragment. The oxidative addition of the Ph ─ S bond in 77 to the Pd(0) center would bring about the cleavage of the C ─ S bond to give 78. The cleaved Ph group would be released as benzene, by protonolysis of the resulting PhPd(OCOAr) species with

ArCO 2H leading to the regeneration of Pd(OCOAr) 2. The product 78 is released in the oxidative addition step, which allows the Pd(II) species to be regenerated, even in the absence of an external oxidant, as is the case for the Pd(II) ─ catalyzed synthesis of phospholes via phosphonium salts (section 3). The substrate scope is shown in Scheme 18. Using these opti- mized conditions, the cyclization of both electron ─ rich and electron ─ poor substrates can be achieved, affording the corre- sponding cyclized products in good to excellent yields. It is noteworthy that a phenolic OH group is tolerated under these conditions (i.e., 78e) because oxidative conditions are not needed for this protocol. Dibenzothiophenes bearing chloro and uoro groups could also be synthesized without the elimi- nation of these groups. In the case of a substrate with a sub- stituent at the 3’ ─ position, the cyclization proceeded at the less ─ hindered position in a site ─ selective manner (i.e., 78i). This strategy allowed unsymmetrical polysubstituted dibenzo- thiophenes to be prepared as well as a benzothienothiophene such as anthraquinone 82b, amino acid 82c and BODIPY 82d ring system, as in 78s. Moreover, using the approach, it is also derivatives. possible to synthesize dibenzoselenophene 78t via the cleavage We next attempted to apply the catalytic C ─ S bond cleav- of a C ─ Se bond. age reaction to an intermolecular heteroannulation process. Our C ─ H/C ─ S coupling methodology could also be applied The catalytic heteroannulation of aniline and phenol deriva- for the late ─ stage introduction of benzothiophene moieties tives with alkynes provides a powerful convergent method for using the boronic acid 80 as an effective elaborating reagent the synthesis of indoles and benzofurans from simple, readily (Scheme 19). Thus, a Suzuki ─ Miyaura reaction with 79, fol- available building blocks. For example, the palladium ─ cata- lowed by ring closure via our C ─ H/C ─ S coupling method lyzed annulation of 2 ─ haloaniline derivatives with alkynes is allowed to a wide variety of π ─ systems to be prepared by known as Larock’s indole synthesis and is in widespread use in fusion with a benzothiophene ring. For example, a bromophe- organic synthesis (Scheme 20). 50 This strategy has also been nyl group in a 2,5 ─ diaryloxadiazole motif can successfully successfully applied to the preparation of the corresponding 51 participate in our two ─ step protocol to form benzothiophene ─ benzofuran derivatives. However, sulfur variants of this type fused derivative 82a. Similarly, this protocol was found to be of heteroannulation have not been reported, although several applicable to the π ─ extension of a range of useful compounds, radical annulation reactions for producing benzothiophene

1192 （ 56 ） J. Synth. Org. Chem., Jpn. Scheme 19. Boronic acid 80 as a versatile reagent for the and aromatic alkynes to be incorporated into benzothiophene incorporation of a fused benzothiophene ring a derivatives (Scheme 21). Several sets of unsymmetrical alkynes into various π ─ systems. NMR yield. also successfully participated in this heteroannulation reaction. Alkyl phenyl acetylenes preferentially provide benzothiophene derivatives with a phenyl group at the 2 ─ position, whereas silyl ─ substituted alkynes predominantly gave benzothiophenes derivatives bearing a silyl group at the 2 ─ position, irrespective of the nature of the substituent at the other terminal. These regioselectivities are similar to those observed in the Larock indole synthesis. In terms of functional group compatibility, chloro, cyano and ketone groups were well ─ tolerated, thus permitting a wide range of functionalized benzothiophenes to be produced. The synthesis of pyridine ─ fused and π ─ extended thiophene derivatives were also found to be accessible by this method.

Scheme 21. Palladium ─ catalyzed synthesis of 2,3 ─ disubstituted benzothiophenes via the annulation of aryl sul des with alkynes.

Scheme 20. Palladium ─ catalyzed annulation of aryl halides bearing an ortho heteroatom groups with alkynes for the synthesis of benzo ─ fused heteroarenes.

derivatives have been reported. 52 Our initial attempt to synthesize benzothiophene via the palladium ─ catalyzed coupling of 2 ─ bromothiophenol with alkynes resulted in only a 9% yield of the annulated product, possibly due to the strong coordination of the SH group to the palladium catalyst. To avoid this, we used SMe or SPh groups, in the hope that C ─ S bond cleavage would occur under these conditions. The desired benzothiophenes were obtained in improved yields when these sul de ─ based substrates were used in place of an SH group. 53 The nature of the base also has a signi cant inuence on the reaction, with DBU being the opti- mal base. A plausible mechanism involves the oxidative addi- tion of the C ─ Br bond of 83 to Pd(0) to give the arylpalladium 84, which then adds to the alkyne to form the palladacycle 85. C ─ S bond forming reductive elimination would then release the sulfonium salt 86 with the regeneration of the Pd(II) spe- cies. The Me group of the sulfonium salt 86 would be removed by a Lewis base present in the reaction system, such as PPh 3, DMF, or an added external base which is used as the solvent, to give the benzothiophene product 88. A control experiment con rmed that S ─ Me bond cleavage of an independently syn- thesized sulfonium salt occurs, even in the absence of a palla- dium catalyst. The optimized conditions allow both aliphatic

Vol.76 No.11 2018 （ 57 ） 1193 Benzothiophene derivatives bearing SiEt 3 group (i.e., 88k as the late ─ stage introduction of these heterole substructures. and 88l) are amenable to further elaboration (Scheme 22). For Given the increasing interest in heterole ─ based materials, example, the treatment of 88l with TFA resulted in desilylation methods that allow the rapid assembly of more elaborate to give 89, which cannot be synthesized directly by the reaction derivatives from readily available starting materials will be with the corresponding terminal alkyne. Iodination by ICl and needed to facilitate structure ─ property relationship studies. a subsequent Suzuki ─ Miyaura coupling with an arylboronic Transition metal catalysis promises to continue to play a vital ester allow access to asymmetrically 2,3 ─ disubstituted benzo- role in this area, and efforts to further contribute to this led thiophenes derivatives in a predictable manner, as demon- are currently underway in our laboratory. strated in the synthesis of 90. Acknowledgements Scheme 22. Transformation of benzothiophene derivative 88l. The authors thank all of the collaborators who were involved in the research described herein. This work was sup- ported, in part, by Scienti c Research on Innovative Area “Hybrid Catalysis” (18H04649) from MEXT, Japan. MT also thanks Tokuyama Science Foundation for nancial support.

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Vol.76 No.11 2018 （ 59 ） 1195 Lett. 2014, 16, 848. (d) Yan, K.; Yang, D.; Wei, W.; Lu, S.; Li, G.; PROFILE Zhao, C.; Zhang, Q.; Wang, H. Org. Chem. Front. 2016, 3, 66. (e) Yugander, S.; Konda, S.; Ila, H. Org. Lett. 2017, 19, 1512. (f) Mitsudo, Takuya Kodama received his PhD from Osa- K.; Kurimoto, Y.; Mandai, H.; Suga, S. Org. Lett. 2017, 19, 2821. ka University in 2018 under the guidance of 48） (a) Che, R.; Wu, Z.; Li, Z.; Xiang, H.; Zhou, X. Chem. Eur. J. 2014, Professor Takashi Kubo. In 2018 he joined 20, 7258. (b) Oechsle, P.; Paradies, J. Org. Lett. 2014, 16, 4086. (c) Professor Tobisu’s group at Osaka University Saito, K.; Chikkade, P. K.; Kanai, M.; Kuninobu, Y. Chem. Eur. J. as an assistant professor. His research inter- 2015, 21, 8365; (d) Huang, Q.; Fu, S.; Ke, S.; Xiao, H.; Zhang, X.; ests are structural and physical organic Lin, S. Eur. J. Org. Chem. 2015, 6602. For the application of C ─ H/ chemistry, in particular, syntheses, properties, C ─ H coupling to the substrates bearing a preinstalled thiophenering, and reactivity of new organic and organome- see: (e) Kaida, H.; Satoh, T.; Hirano, K.; Miura, M. Chem. Lett. 2015, tallic compounds. 44, 1125. (f) Mitsudo, K.; Kurimoto, Y.; Mandai, H.; Suga, S. Org. Lett. 2017, 19, 2821. 49） Tobisu, M.; Masuya, Y.; Baba, K.; Chatani, N. Chem. Sci. 2016, 7, 2587 Naoto Chatani received his PhD in 1984 un- 50） The rst report: (a) Larock, R. C.; Kgun Yum, E. J. Am. Chem. Soc. der Professors Noboru Sonoda and Shinji 1991, 113, 6689. Reviews: (b) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, Murai. In 1984 he joined the Institute of Sci- 111, PR215. (c) Platon, M.; Amardeil, R.; Djakovitch, L.; Hierso, enti c and Industrial Research at Osaka J. ─ C. Chem. Soc. Rev. 2012, 41, 3929. (d) Guo, T.; Huang, F.; Yu, L.; University, where he was an Assistant Profes- Yu, Z. Tetrahedron Lett. 2015, 56, 296. sor in the laboratory of Professor Terukiyo 51） The rst report: (a) Larock, R. C.; Yum, E. K.; Doty, M. J.; Sham, K. Hanafusa. After postdoctoral studies (1988 ─ K. C. J. Org. Chem. 1995, 60, 3270. A review: (b) Abu ─ Hashem, A. 1989 under Professor Scott E. Denmark at A.; Hussein, H. A. R.; Aly, A. S.; Gouda, M. A. Synth. Commun. the University of Illinois, Urbana ─ Cham- 2014, 44, 2285. paign), he moved back to Osaka University 52） Other catalytic intermolecular methods for the synthesis of benzo- and was promoted to the rank of Associate thiophenes: (a) Inami, T.; Baba, Y.; Kurahashi, T.; Matsubara, S. Org. Professor in 1992 and to Full Professor in Lett. 2011, 13, 1912. (b) Yan, K.; Yang, D.; Zhang, M.; Wei, W.; Liu, 2003. He is a recipient of The Chemical Soci- Y.; Tian, L.; Wang, H. Synlett 2015, 26, 1890. (c) Yamauchi, T.; ety of Japan Award for Young Chemists Shibahara, F.; Murai, T. Tetrahedron Lett. 2016, 57, 2945. (1990), The Green & Sustainable Chemistry 53） Masuya, Y.; Tobisu, M.; Chatani, N. Org. Lett. 2016, 18, 4312. Award from the Minister of Education, Cul- ture, Sports, Science and Technology (2005), The Nagoya Silver Medal (2013), The Chemi- cal Society of Japan Award (2017), a Hum- boldt Research Award (2017), and as a Clari- vate Analytics Highly Cited Researcher (2017) and is a recipient of an Arthur C. Cope Scholar Award (2018).

Mamoru Tobisu received his PhD from Osaka University under the direction of Prof. Shinji Murai (2001). During his PhD studies, he was a visiting scientist for ve months (1999) with Prof. Gregory C. Fu at the Massachu- setts Institute of Technology. Following a pe- riod as a scientist at the Takeda Pharmaceuti- cal Company (2001 ─ 2005), he started his academic career at Osaka University in 2005 He was then appointed as an associate pro- fessor at the Center for Atomic and Mole- cular Technologies at Osaka University in 2011 and was promoted to full professor at the Department of Applied Chemistry of Osaka University in 2017. He received the Chemical Society of Japan Award for Young Chemists in 2009, the Young Scientists’ Award, a Commendation for Science and Technology from the Minister of Education, Culture, Sports, Science and Technology in 2012, the Merck ─ Banyu Lectureship Award in 2012, Thomson Reuters Research Front Award in 2016, and the Mukaiyama Award in 2018.

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